Non-Orthogonal Particle Detection Systems and Methods

ABSTRACT

Described herein is a particle detection system capable of spatially resolving the interaction of particles with a beam of electromagnetic radiation. Using a specific electromagnetic beam cross sectional shape and orientation, the detection sensitivity of a particle detection system can be improved. Also provided are methods for detecting and sizing particles in a manner that has low background signal and allows for spatially resolving the scattering or emission of electromagnetic radiation from particles.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Patent Application Nos. 61/005,336, 60/992,192 and61/107,397 filed on Dec. 4, 2007, Dec. 4, 2007, and Oct. 22, 2008,respectively, which are hereby incorporated by reference in theirentireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

BACKGROUND OF THE INVENTION

This invention is in the field of optical particle counters. Thisinvention relates generally to an optical particle counter capable ofspatially resolving electromagnetic radiation scattered off of oremitted by particles. This invention also relates to methods fordetecting and sizing particles and methods for spatially resolving aninteraction of particles with a beam of electromagnetic radiation

A large portion of the micro-contamination industry is reliant on theuse of particle counters, such as are described in a large number ofU.S. patents, including U.S. Pat. Nos. 3,851,169, 4,348,111, 4,957,363,5,085,500, 5,121,988, 5,467,188, 5,642,193, 5,864,399, 5,920,388,5,946,092, and 7,053,783. U.S. Pat. Nos. 4,728,190, 6,859,277, and7,030,980, 5,282,151 also disclose particle counters and are herebyincorporated by reference in their entirety. Aerosol particle countersare often used to measure air-born particle contamination in clean-roomsand clean zones. Liquid phase particle counters are often used tomeasure particulate contamination in the water treatment and chemicalprocessing industries.

Particle counters capable of spatially resolving electromagneticradiation scattered or emitted by particles typically employtwo-dimensional detectors, such as the particle detector described inU.S. Pat. No. 5,282,151. U.S. Pat. No. 7,170,601 and U.S. PatentApplication Publication No. US 2006/0001874 A1 also disclose a particlecounter capable of spatially resolving electromagnetic radiationscattered or emitted by particles. These optical particle counterscollect scattered or emitted electromagnetic radiation in a directionparallel to the fluid flow direction and are capable of spatiallyresolving the source of scattered or emitted electromagnetic radiationalong directions perpendicular to the fluid flow direction. Theseparticle counters, however, lack the ability to spatially resolvescattered or emitted electromagnetic radiation in a direction parallelto the fluid flow direction. The particle detection systems describedherein utilize a geometrical configuration which allows for spatiallyresolving electromagnetic radiation scattered or emitted by particles indirections parallel to the fluid flow direction as well as perpendicularto the fluid flow direction.

SUMMARY OF THE INVENTION

Described herein is a particle detection system capable of spatiallyresolving the interaction of particles with a beam of electromagneticradiation. Using a specific electromagnetic beam cross sectional shapeand orientation, the detection sensitivity of a particle detectionsystem can be improved. Also described herein are methods for detectingand sizing particles in a manner that has low background signal andallows for spatially resolving the scattering or emission ofelectromagnetic radiation from particles.

In an embodiment, a particle detection system comprises a flow cell forcontaining a fluid flowing through the flow cell in a flow direction; asource for generating a beam of electromagnetic radiation having a crosssectional profile having a major axis and a minor axis, the sourcepositioned to direct the beam through the flow cell, wherein the anglebetween the major axis of the cross sectional profile of the beam andthe flow direction is non-orthogonal, and wherein particles containedwithin the fluid interact with the beam thereby generating scattered oremitted electromagnetic radiation; and a two-dimensional detectorpositioned in optical communication with the flow cell for receiving atleast a portion of the scattered or emitted electromagnetic radiation.

Particle detection systems such as these are useful with methods ofdetecting and/or sizing particles. In an embodiment, a method of thisaspect comprises the steps of: providing particles in a fluid having aflow direction; passing a beam of electromagnetic radiation having across sectional profile having a major axis and a minor axis through thefluid, wherein the angle between the major axis and the flow directionis non-orthogonal and wherein particles interact with the beam therebygenerating scattered or emitted electromagnetic radiation; and detectingat least a portion of the scattered or emitted electromagnetic radiationwith a two-dimensional detector, thereby detecting the particles. In anembodiment preferred for some applications, the scattered or emittedelectromagnetic radiation is collected or directed onto thetwo-dimensional detector by a system of optics. In some embodiments, theangle between the beam cross sectional major axis and the flow directionis non-parallel.

Any optical element may be useful with the methods and systems describedherein including, but not limited to: a lens, a mirror, a filter, a beamsplitter, an optical fiber, an optical waveguide, a window, an aperture,a slit, a prism, a grating, a polarizer, a wave plate, a crystal, andany combination of these or other optical elements. In an embodimentpreferred for some applications, the scattered or emittedelectromagnetic radiation is imaged onto the two-dimensional detector bythe system of optics. For some embodiments, a particle counteroptionally includes auto-focusing of the system of optics to properlyimage scattered or emitted radiation from a particle onto atwo-dimensional detector.

In an embodiment preferred for some applications, useful two-dimensionaldetectors comprise an array of detector elements positioned such that aplurality of detector elements receive the scattered or emittedelectromagnetic radiation. Any two-dimensional detector can be usefulwith the systems and methods for detecting or sizing particlesincluding, but not limited to: a two-dimensional array ofphotodetectors, a charge-coupled device (CCD) detector, a complementarymetal-oxide-semiconductor (CMOS) detector, a metal-oxide-semiconductor(MOS) detector, an active pixel sensor, a microchannel plate detector, atwo-dimensional array of photomultiplier tubes, a two-dimensional arrayof photodiodes, a two-dimensional array of phototransistors, atwo-dimensional array of photoresistors, and a photoconductive film.

In embodiments preferred for some applications, the two-dimensionaldetector has an orientation positioned to allow for a sharply focusedimage of the scattered or emitted electromagnetic radiation across anactive area of the two-dimensional detector. In an embodiment preferredfor some applications, the two-dimensional detector has an orientationpositioned for providing a spatially resolved image of the scattered oremitted electromagnetic radiation, wherein the scattered or emittedelectromagnetic radiation is spatially resolved in a first directionparallel to a propagation axis of the beam and in a second directionparallel to the flow direction. In another embodiment, the orientationof the two-dimensional detector provides for a spatially resolved imageof the scattered or emitted electromagnetic radiation in a firstdirection parallel to a propagation axis of the beam and in a seconddirection parallel to the major axis of the beam cross sectionalprofile.

In another aspect, methods are provided for spatially resolving aninteraction of particles with a beam of electromagnetic radiation. Amethod of this aspect comprises the steps of: providing particlessuspended within a fluid flowing in a flow direction; passing a beam ofelectromagnetic radiation through the fluid, wherein the beam has across sectional profile having a major axis and a minor axis and whereinthe angle between the major axis and the flow direction isnon-orthogonal and wherein the particles interact with the beam therebygenerating scattered or emitted electromagnetic radiation; and directingat least a portion of the scattered or emitted electromagnetic radiationonto a two-dimensional detector, thereby spatially resolving thescattered or emitted electromagnetic radiation in a first directionparallel to a propagation axis of the beam and in a second directionparallel to the major axis of the beam cross sectional profile. Forembodiments, when the scattered or emitted electromagnetic radiationreaches the two-dimensional detector, it is detected by thetwo-dimensional detector, thereby generating a plurality of outputsignals corresponding to intensities of the scattered or emittedelectromagnetic radiation. In some embodiments, the angle between thebeam cross sectional major axis and the flow direction is non-parallel.

In an embodiment preferred for some applications, the electromagneticradiation scattered or emitted by the particles is spatially resolvedfrom electromagnetic radiation scattered or emitted by walls of a flowcell surrounding the fluid. In another embodiment, electromagneticradiation scattered or emitted by a first particle interacting with thebeam is imaged onto a first position of the two-dimensional detector andscattered or emitted electromagnetic radiation generated by a secondparticle, having a different position than the first particle, is imagedonto a second position of the two-dimensional detector.

In some embodiments of this aspect, the method further comprisesanalyzing a signal provided by the detector in response to the scatteredor emitted electromagnetic radiation. In an embodiment, the analysiscomprises one or more techniques including time delay integration (TDI),image threshold analysis, image shape analysis, pulse height analysis,pulse width analysis, or other techniques useful for detectingparticles.

In another aspect, methods are provided for sizing a particle. A methodof this aspect comprises the steps of: providing a particle suspendedwithin a fluid flowing in a flow direction through a flow cell; passinga beam of electromagnetic radiation through the fluid, wherein the beamhas a cross sectional profile having a major axis and a minor axis andwherein the angle between the major axis and the flow direction isnon-orthogonal and wherein the particle interacts with the beam therebygenerating scattered or emitted electromagnetic radiation; imaging atleast a portion of the scattered or emitted electromagnetic radiationonto a two-dimensional detector; determining the intensity of thescattered or emitted electromagnetic radiation on the two-dimensionaldetector; and comparing the intensity of the scattered or emittedelectromagnetic radiation with one or more threshold reference values,thereby determining the size of the particle. For example, the thresholdreference values may correspond to intensities of scattered or emittedelectromagnetic radiation from particles of known sizes; if theintensity of electromagnetic radiation scattered or emitted from aparticle falls between two threshold reference values, the particle issized between the known particle sizes corresponding to those thresholdreference values.

In an embodiment of this aspect, the threshold reference values aredependent upon the position of the particle within the flow cell. Inanother embodiment, the threshold reference values are dependent uponthe flow rate of the fluid. In yet another embodiment, the flow rate ofthe fluid may be dependent upon the position within the flow cell; forexample, fluid flowing near the walls of the flow cell may be flowingslower than fluid flowing near the center of the flow cell. In anotherembodiment, the threshold reference values are dependent upon theintensity of the beam. In a further embodiment, the threshold referencevalues are dependent upon both the intensity of the beam and theposition within the flow cell.

In an embodiment preferred for some applications, the method may furthercomprise the step of determining the position of the particle within theflow cell. In some embodiments, this step is preferred to occur beforethe step of comparing the intensity of the scattered or emittedelectromagnetic radiation with one or more threshold reference values.In another embodiment, the position of the particle within the flow cellis used to determine one or more threshold reference values forsubsequent comparison.

Without wishing to be bound by any particular theory, there can bediscussion herein of beliefs or understandings of underlying principlesrelating to the invention. It is recognized that regardless of theultimate correctness of any mechanistic explanation or hypothesis, anembodiment of the invention can nonetheless be operative and useful.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a schematic diagram of an embodiment of a particledetection system.

FIG. 2A provides a perspective view of an embodiment of a particledetection system.

FIG. 2B provides a perspective view of an embodiment of a particledetection system.

FIG. 3A shows an alternative perspective of a beam of electromagneticradiation illuminating a flow cell in a particle detection system.

FIG. 3B shows an expanded view of a region of FIG. 3A.

FIG. 3C shows an overhead view of the flow cell of FIG. 3A.

FIG. 3D shows a view of the flow cell of FIG. 3A along the fluid flowdirection.

FIG. 3E shows a side view of the flow cell of FIG. 3A.

FIG. 4A shows an image detected by a two-dimensional detector of aparticle detection system, where the angle between the beam crosssectional profile major axis and the flow direction is 90°.

FIG. 4B shows an image detected by a two-dimensional detector of aparticle detection system, where the angle between the beam crosssectional profile major axis and the flow direction is 45°.

FIG. 4C shows an image detected by a two-dimensional detector of aparticle detection system, where the angle between the beam crosssectional profile major axis and the flow direction is 21°.

FIG. 5 shows data illustrating the counting efficiency of 80 nmparticles by a particle detection system at various angles between thebeam cross sectional profile major axis and the flow direction.

FIG. 6 shows data illustrating the counting efficiency of 125 nmparticles by a particle detection system at various angles between thebeam cross sectional profile major axis and the flow direction.

FIG. 7 shows data summarizing the counting efficiency of 80 and 125 nmparticles at various angles between the beam cross sectional profilemajor axis and the flow direction.

FIG. 8 shows views of an exemplary capillary mount.

FIG. 9 illustrates an exemplary autofocus system.

DETAILED DESCRIPTION OF THE INVENTION

In general the terms and phrases used herein have their art-recognizedmeaning, which can be found by reference to standard texts, journalreferences and contexts known to those skilled in the art. The followingdefinitions are provided to clarify their specific use in the context ofthe invention.

“Flow direction” refers to an axis parallel to the direction the bulk ofa fluid is moving when a fluid is flowing. For fluid flowing through astraight flow cell, the flow direction is parallel to the path the bulkof the fluid takes. For fluid flowing through a curved flow cell, theflow direction may be considered tangential to the path the bulk of thefluid takes.

“Beam propagation axis” refers to an axis parallel to the direction oftravel of a beam of electromagnetic radiation.

“Cross sectional profile” refers to a profile formed by a plane cuttingthrough an object at a right angle to an axis of propagation or travel.For example the cross sectional profile of a beam of electromagneticradiation is a profile of the beam formed by a plane perpendicular tothe beam propagation axis. The cross sectional profile of a flow cell isa profile of the flow cell formed by a plane perpendicular to the flowdirection.

“Major axis” refers to an axis parallel to the longest axis of a shape.For example, the major axis of an ellipse is parallel to the longestdiameter of the ellipse, and the major axis of a rectangle is parallelto the long dimension of a rectangle.

“Minor axis” refers to an axis parallel to the shortest axis of a shape.For example, the minor axis of an ellipse is parallel to the shortestdiameter of the ellipse, and the minor axis of a rectangle is parallelto the short dimension of a rectangle.

“Optical communication” refers to an orientation of components such thatthe components are arranged in a manner that allows light orelectromagnetic radiation to transfer between the components.

“Optical axis” refers to a direction along which electromagneticradiation propagates through a system.

“Spot size” refers to the size that an image of a point or object isfocused to by one or more lenses. In general, the spot size refers tothe root mean square (RMS) spot size. The RMS spot size is the size of aspot which includes 66% of the total energy, for example 66% of thetotal energy of a focused beam of electromagnetic radiation.

“Two-dimensional detector” refers to a detector capable of spatiallyresolving input signals (e.g., electromagnetic radiation) in twodimensions across an active area of the detector. A two-dimensionaldetector is capable of generating an image, for example an imagecorresponding to an intensity pattern on the active area of thedetector. A preferred two-dimensional detector comprises an array ofdetector elements or pixels, for example: a two-dimensional array ofphotodetectors, a charge-coupled device (CCD) detector, a complementarymetal-oxide-semiconductor (CMOS) detector, a metal-oxide-semiconductor(MOS) detector, an active pixel sensor, a microchannel plate detector, atwo-dimensional array of photomultiplier tubes, a two-dimensional arrayof photodiodes, a two-dimensional array of phototransistors, atwo-dimensional array of photoresistors, or a photoconductive film.

“Particle” refers to a small object which is often regarded as acontaminant. A particle can be any material created by the act offriction, for example when two surfaces come into mechanical contact andthere is mechanical movement. Particles can be composed of aggregates ofmaterial, such as dust, dirt, smoke, ash, water, soot, metal, minerals,or any combination of these or other materials or contaminants.“Particles” may also refer to biological particles, for example,viruses, spores and microorganisms including bacteria, fungi, archaea,protists, other single cell microorganisms and specifically thosemicroorganisms having a size on the order of 1-15 μm. A particle mayrefer to any small object which absorbs or scatters light and is thusdetectable by an optical particle counter. As used herein, “particle” isintended to be exclusive of the individual atoms or molecules of acarrier fluid, for example water molecules, oxygen molecules, heliumatoms, nitrogen molecules, etc. Some embodiments of the presentinvention are capable of detecting, sizing, and/or counting particlescomprising aggregates of material having a size greater than 50 nm, 100nm, 1 μm or greater, or 10 μm or greater. Specific particles includeparticles having a size selected from 50 nm to 50 μm, a size selectedfrom 100 nm to 10 μm, or a size selected from 500 nm to 5 μm.

A particle detection system of some embodiments comprises a flow cellfor containing a fluid flowing through the flow cell in a flowdirection. In an embodiment preferred for some applications, the flowcell comprises a transparent-walled sample cell. Useful flow cellscomprise flow cells capable of transporting fluids comprising liquids orgases. The flow direction of the fluid also provides a reference axisuseful for defining additional components of the systems and methodsdescribed herein. In an embodiment, the flow cell has a cross sectionalprofile having a first longer side and a second shorter side. In someembodiments, the first longer side has a length selected from the rangeof 0.25 mm to 10 mm, preferably 5 mm. In some embodiments, the secondshorter side has a width selected from the range of 80 μm to 500 μm,preferably 100 μm. In an embodiment, the flow cell cross section has anaspect ratio, equal to the length of the longer side divided by thewidth of the shorter side, greater than or equal to 20, or greater thanor equal to 50. In some embodiments, the first longer side of the flowcell is aligned parallel to an electromagnetic beam propagation axis andthe second shorter side of the flow cell is aligned perpendicular to anelectromagnetic beam propagation axis.

A particle detection system of some embodiments also comprises a sourcefor generating a beam of electromagnetic radiation. In a preferredembodiment, the beam of electromagnetic radiation has a cross sectionalprofile having a major axis and a minor axis. Such a cross sectionalprofile may be generated by the source itself or by the source incombination with one or more beam shaping elements including lenses,mirrors, apertures, or other beam shaping elements. In some embodiments,the beam cross sectional profile has an elliptical or rectangular shape.In other embodiments, the beam cross sectional profile has a shape thatis substantially elliptical or substantially rectangular. In anembodiment preferred for some applications, the beam cross sectionalprofile has a width along the minor axis selected from between 5 μm and100 μm, preferably 40 μm. In another embodiment preferred for someapplications, the beam cross sectional profile has a width along themajor axis selected from between 50 μm and 1200 μm, preferably 600 μm.In an exemplary embodiment, the beam cross sectional profile has a widthalong the major axis which extends to or beyond the walls of the flowcell. In this and other embodiments, the particle detection system iscapable of providing a volumetric analysis of the fluid. In anotherembodiment, the beam cross sectional profile has a width along the majoraxis which does not reach the walls of the flow cell. In this and otherembodiments, the particle detection system is capable of providing anon-volumetric analysis of the fluid.

In a preferred embodiment, the source is positioned to direct the beamthrough a flow cell such that the angle between the major axis of thebeam cross sectional profile and the flow direction is non-orthogonal.For some embodiments, the angle between the major axis of the beam crosssectional profile and the flow direction is selected from the range of5° to 85°, or preferably from the range of 16° to 26°, or morepreferably from the range of 20° to 22°. In some embodiments, however,the beam cross profile major axis may be orthogonal or parallel to theflow direction.

The particle detection systems in another embodiment further comprise atwo dimensional detector positioned in optical communication with theflow cell. A detector positioned in optical communication with the flowcell is useful for detecting at least a portion of electromagneticradiation that is scattered or emitted by particles interacting with thebeam. In an embodiment preferred for some applications, thetwo-dimensional detector comprises an array of detector elementspositioned such that a plurality of detector elements receives at leasta portion of the scattered or emitted electromagnetic radiation. Usefultwo-dimensional detectors include, but are not limited to: atwo-dimensional array of photodetectors, a CCD detector, a CMOSdetector, a MOS detector, an active pixel sensor, a microchannel platedetector, a two-dimensional array of photomultiplier tubes, atwo-dimensional array of photodiodes, a two-dimensional array ofphototransistors, a two-dimensional array of photoresistors, and aphotoconductive film.

Some embodiments of this aspect may further comprise a system of optics.Optical elements of such a system are useful for shaping the beam ofelectromagnetic radiation, or for collecting or directingelectromagnetic radiation scattered or emitted by particles interactingwith the beam onto the two-dimensional detector. A system of optics maycomprise one or more optical elements. For example, a system of opticsmay comprise two aspherical lenses. Useful optical elements include: alens, a mirror, a filter, a beam splitter, an optical fiber, an opticalwaveguide, a window, an aperture, a slit, a prism, a grating, apolarizer, a wave plate, a crystal, and any combination of these orother shaping, focusing, or directing elements. In an embodimentpreferred for some applications, the system of optics images thescattered or emitted radiation onto the two-dimensional detector. Inanother embodiment, the scattered or emitted electromagnetic radiationis focused to a spot on the two-dimensional detector having a sizeselected from the range of 5 μm to 80 μm, preferably 12 μm.

A system of optics for collecting or directing the scattered or emittedelectromagnetic radiation is preferably positioned between the flow celland the two-dimensional detector. In an embodiment, the two-dimensionaldetector is oriented non-orthogonal to the optical axis of the system ofoptics for collecting or directing the beam onto the two dimensionaldetector. Non-orthogonal in this embodiment is in reference to theposition of the plane of the two-dimensional detector which contains theactive elements in relation to the optical axis of the system of optics.

In another embodiment, the optical axis of the system of optics isoriented non-orthogonal to the major axis of the beam cross sectionalprofile. In an exemplary embodiment, the two-dimensional detector has anorientation positioned to allow for a sharply focused image of thescattered or emitted electromagnetic radiation across an active area ofthe two-dimensional detector. In another exemplary embodiment, the twodimensional detector has an orientation positioned for providing aspatially resolved image of the scattered or emitted electromagneticradiation, wherein the scattered or emitted electromagnetic radiation isspatially resolved along a first axis parallel to the beam propagationaxis and along a second axis parallel to the major axis of the beamcross sectional profile.

Referring now to the drawings, FIG. 1 shows a schematic diagram of anembodiment of a particle detection system. As seen in the Figure, source100 generates a beam of electromagnetic radiation 110 directed throughflow cell 120 parallel to beam propagation axis 115. In this embodiment,beam 110 is shaped and directed by a lens 130 before entering flow cell120. Particles suspended in the fluid flowing through flow cell 120generate scattered or emitted electromagnetic radiation 160 when theyinteract with beam 110. An optical system 170 collects and focuses thescattered or emitted electromagnetic radiation 160 along opticaldetection axis 175 and onto a two-dimensional detector 180. In thisembodiment, optical system 170 is comprised of two aspheric lenses.

FIG. 2A shows a perspective view of a particle detection systemembodiment. In this embodiment, source 200 generates a beam ofelectromagnetic radiation 210 which is directed through flow cell 220.Beam 210 is shaped and directed by a lens 230 before entering flow cell220. In this embodiment, beam 210 is shaped by lens 230 to have a crosssectional profile 235 having an elliptical shape having a major axisparallel to axis 205 and a propagation axis orthogonal to flow direction250. Particles 240 flow through flow cell 220 parallel to flow direction250. Cross sectional profile major axis 205 forms an angle 290 with flowdirection 250. Particles flow through the region of the flow cell 220that is illuminated by beam 210 and interact with the beam, generatingscattered or emitted electromagnetic radiation 260. Scattered or emittedelectromagnetic radiation 260 is collected and directed by opticalsystem 270 onto two-dimensional detector 280 along optical detectionaxis 275. In this embodiment, two-dimensional detector 280 isnon-orthogonal to optical detection axis 275.

FIG. 2B shows a perspective view of an alternative particle detectionsystem embodiment. In this embodiment, source 200 generates a beam ofelectromagnetic radiation 210 which is directed through flow cell 220.Beam 210 is shaped and directed by a lens 230 before entering flow cell220. In this embodiment, beam 210 is shaped by lens 230 to have a crosssectional profile 235 having an elliptical shape having a major axisparallel to axis 205 and a propagation axis non-orthogonal to flowdirection 250. Particles 240 flow through flow cell 220 parallel to flowdirection 250. In this embodiment, flow direction 250 and crosssectional profile major axis 205 are orthogonal. Particles flow throughthe region of the flow cell 220 that is illuminated by beam 210 andinteract with the beam, generating scattered or emitted electromagneticradiation 260. Scattered or emitted electromagnetic radiation 260 iscollected and directed by optical system 270 onto two-dimensionaldetector 280 along optical detection axis 275. In this embodiment,two-dimensional detector 280 is non-orthogonal to optical detection axis275.

FIG. 3A shows an alternative perspective view of the beam ofelectromagnetic radiation illuminating the flow cell. In this figure,beam 310 is traveling parallel to beam propagation axis 315. Particlesand fluid flowing in flow cell 320 travel parallel to flow direction350. FIG. 3B shows an expanded view of a region of flow cell 320.Particles 340 travel parallel to flow direction 350 along trajectories355 and interact with beam 310 in regions 365 where they generatescattered or emitted electromagnetic radiation. FIGS. 3C, 3D, and 3Eshow various views of the flow cell 320 and beam 310. FIG. 3C shows aview of the flow cell 320 and beam looking along the propagation axis ofthe beam. The cross sectional profile 335 of the beam is shown in thisview. In this embodiment, cross sectional profile 335 has an ellipticalshape. FIG. 3C also shows a set of axes for this view showing flowdirection 350, an optical collection axis 375 and beam cross sectionalprofile major axis 305. Angle 390 is formed between flow direction 350and beam cross sectional profile major axis 305. In various embodiments,angle 390 is different from 90°; that is, flow direction 350 and beamcross sectional profile major axis 305 are non-orthogonal. In someembodiments, however, angle 390 is 90°. FIG. 3D shows a view of flowcell 320 looking along flow direction. Beam 310 propagates along beampropagation axis 315 illuminating flow cell 320. Scattered or emittedelectromagnetic radiation generated by particles interacting with beam310 is collected along optical collection axis 375. FIG. 3E shows a viewalong the optical collection axis. Particles and fluid flow in flowdirection 350 through flow cell 320. Beam 310 propagates along beampropagation axis 315 illuminating flow cell 320. In this embodiment,only a small portion of flow cell 320 is illuminated by beam 310. Theilluminated region is indicated by the dashed lines in FIG. 3E. However,all of the fluid flows through the beam.

The invention may be further understood by the following non-limitingexample:

Example 1 Particle Detector Images and Counting Efficiencies

FIGS. 4A, 4B, and 4C show images detected by a two-dimensional detectorof a particle detection system embodiment for various angles between theflow direction and beam cross sectional profile major axis. Thesegrey-scale images represent intensities observed by a two-dimensionaldetector where black is low intensity and white is high intensity. Theseimages represent a view of the flow cell similar to that of FIG. 3E. Inthese images, the bright white spot at the top of the image representsscattered or emitted electromagnetic radiation generated by the beaminteracting with the walls of the flow cell where the beam enters theflow cell. The bright white spot at the bottom of the image representsscattered or emitted electromagnetic radiation generated by the beaminteracting with the walls of the flow cell where the beam exits theflow cell. In these images, particles having a size of 125 nm aretravelling in the fluid along flow direction 350, and the beam ispropagating along axis 315. The insets in these images show views of theflow cell along the beam propagation axis, showing the orientation ofthe beam cross sectional profile major axis 305 in relation to the flowcell and flow direction 350.

In FIG. 4A, beam cross sectional profile major axis 305 is perpendicularto flow direction 350; i.e., angle 390 is 90°. The bright white spot inthe center of the image is a result of contamination on the walls of theflow cell. The faint line travelling from the top of the image to thebottom of the image represents electromagnetic radiation scattered byfluid in the flow cell interacting with beam which propagates along axis315. In the image in FIG. 4A, a faint spot brighter than itssurroundings may indicate detection of a single particle (indicated byan arrow in the image). The bright white spot is likely the result ofcontamination located on the walls of the flow cell interacting with thebeam. In this orientation, electromagnetic radiation scattered oremitted by contamination such as this falls along regions of the flowwhere particles may travel, thus obscuring detection of particles fromthese region. When angle 390 is different from 90°, contamination on thewalls of the flow cell will be appear towards the left or right side ofthe image and not obscure such large regions.

In FIG. 4B, beam cross sectional profile major axis 305 and flowdirection 350 form an angle 390 of approximately 45°. The two brightwhite spots along the left side of the image are a result ofcontamination on the walls of the flow cell. As mentioned before, sincethe cross-sectional profile of the beam is now at an angle 390 of 45°,the scattered or emitted electromagnetic radiation from thecontamination no longer obscures major portions of the flow region, butappears at the sides of the image. The faint glow travelling from thetop of the image to the bottom of the image represents electromagneticradiation scattered by fluid in the flow cell interacting with beampropagating along axis 315. In the image in FIG. 4B, several faint spotsbrighter than the surroundings may indicate detection of particles (3examples indicated by arrows in the image). With the geometricalconfiguration of FIG. 4A, where angle 390 is 90°, the particle indicatedby the long arrow would likely be obscured from detection due to thetopmost bright contamination spot located on the left side of the image.This shows a useful advantage of the non-orthogonal geometry in reducingnoise and increasing detection efficiency and sensitivity. Additionally,when beam cross sectional profile major axis 305 is non-orthogonal toflow direction 350, such as in FIG. 4B, the location that scattered oremitted radiation is detected on the two-dimensional detector is relatedto the position of the origin of the scattered or emitted radiation inthe flow cell. For example, the bright contamination spot on the leftside of the image appears to be from contamination on one side of theflow cell, as indicated by element 395 in the inset, while the particleindicated by the long arrow appears to be from a particle travellingnear the opposite side of the flow cell, as indicated by element 340 inthe inset.

In FIG. 4C, beam cross sectional profile major axis 305 is aligned toflow direction 350 at an angle 390 of approximately 21°. The faint glowtravelling from the top of the image to the bottom of the imagerepresents electromagnetic radiation scattered by fluid in the flow cellinteracting with beam propagating along axis 315. In the image in FIG.4C, several faint spots brighter than the surroundings indicatedetection of particles (5 examples indicated by arrows in the image).Aside from separating scattered or emitted electromagnetic radiationfrom the walls of the walls of the flow cell, when beam cross sectionalprofile major axis 305 is non-orthogonal to flow direction 350, theparticles have a longer distance to travel through the beam, resultingin more light scattered and smaller particles able to be detected.

Polystyrene latex particles having sizes of 80 nm and 125 nm wereallowed to flow through a particle detection system in order todetermine the counting efficiency of the particles. The angle betweenthe flow direction and the beam cross sectional profile major axis wasvaried at 3 directions: a 21° angle between the flow direction and thebeam cross sectional profile major axis; a 45° angle between the flowdirection and the beam cross sectional profile major axis; and a 90°angle between the flow direction and the beam cross sectional profilemajor axis. FIG. 5 shows data illustrating the counting efficiency of 80nm particles as a function of the angle between the flow direction andbeam cross sectional profile major axis. As seen in FIG. 5, the countingefficiency of the 80 nm particles drops as the angle is increased from21° to 45° to 90°. FIG. 6 shows similar data illustrating the countingefficiency of 125 nm particles. As seen in FIG. 6, the countingefficiency of 125 nm particles is near 100% at 21° and 45°, but has asignificant drop off to less than 80% counting efficiency at an angle of90°. FIG. 7 summarizes the counting efficiency of 80 nm and 125 nmpolystyrene latex particles.

Example 2 Capillary Mount for Particle Counting with Integral Seals

One issue that has plagued liquid particle counters is the lack of achemically resistant seal for sealing sample capillaries to a flow cell.An approach to solve this problem uses a holder or a mount comprising anonreactive and virtually rigid polymer, for example Kel-f at 80 ShoreD, to create a seal with a capillary inlet. The holder or mount includesone or more concentric seals around a capillary aperture integral to theholder or mount. This cuts the number of potential leak paths,eliminates components that can be incorrectly installed and reduces thenumber of tolerances to insure a more uniform seal pressure. Inembodiments, a particle counter or particle detection system comprisessuch a capillary mount.

Imaging-based particle counters of the present invention optionallyinclude capillary mounts for particle counting with integral seals, forexample, using a rigid polymer (e.g., Kel-f at 80 Shore D) that isformed either by machining or molding to create a series of concentricseals around a capillary aperture integral to the holder. Use of acapillary mount with an integral seal is beneficial for someapplications as it cuts the number of potential leak paths, eliminatescomponents that can be incorrectly installed and reduces the number oftolerances to ensure a more uniform seal pressure.

FIG. 8 illustrates a perspective view of an exemplary capillary mount800. Capillary mount 800 includes a plurality of sealing regions 801 forcreating a seal with capillary. Capillary mount 800 also includes a flowcell and a plurality of window regions 802 for permitting the entry andexit of a laser beam into the flow cell. Additional window regions 803are included for transmitting scattered light to a detector. For someembodiments, capillary mount 800 is a unitary structure; that is itcomprises a single piece of material for forming a seal with one or morecapillaries.

Example 3 Autofocus of Non-Orthogonal Particle Detector

In order to maximize particle transit time, coverage area and minimizedepth of field, the laser path in a particle detector is tipped relativeto a capillary cell. In one embodiment, the beam cross sectional profilemajor axis is oriented non-orthogonal to the flow direction within thecapillary cell. In another embodiment, the beam propagation axis isoriented non-orthogonal to the flow direction within the capillary cell.For example, these axes can be oriented at a relative angle of 69° or21°. In order to collect the radiation scattered from or emitted byparticles in the flow and ensure a proper focus, the detector andcapillary are tipped relative to any sensor imaging optics, for examplea system of optics as described above. Imaging-based particle countersof the present invention optionally include auto-focusing eitherparticle spot sizes or laser beam structure or a combination of both.

The location of the detector along the optical axis of the imagingoptics can be adjusted by translation to achieve the best focus of thescattered or emitted radiation, but must also keep the image in the samelocation on the detector throughout the range of translation. A methodfor achieving this comprises mounting the detector at a fixed angle tothe optical axis of the imaging optics and translating the detectoralong the imaging axis to focus. In one embodiment, the detector ismounted on a linear rail system aligned to the optical axis fortranslating the detector along the optical axis. In a specificembodiment, a spring is mounted to preload the imaging optics againstone side of an angled plane to increase the precision of a translationstepper motor (e.g., by a factor of 5 or greater), to allow for asmaller increment of linear motion (e.g., 2 μm or less) per steppermotor step. In an embodiment, a particle counter or particle detectionsystem comprises an autofocus system.

FIG. 9 illustrates a specific autofocusing system embodiment 900. Acapillary cell is mounted in capillary mount 901 and detector 902 ismounted at an angle relative to imaging optics housed within block 903.A linear rail system 904 is attached to detector 902 and stepper motor905 for translation of detector 902 along the optical axis of theimaging optics housed within block 903.

Example 3 Detector Array Processing

In embodiments, electromagnetic radiation is scattered from or emittedby a particle interacting with a beam of electromagnetic radiation of aparticle detection system; scattered or emitted electromagneticradiation which reaches the two-dimensional detector is detected,thereby generating a plurality of output signals corresponding tointensities of the scattered or emitted electromagnetic radiation. Theseoutput signals can be further processed and/or analyzed to determine acharacteristic of the particle.

For some embodiments, output signals from every element of thetwo-dimensional detector are recorded or transmitted to a processor forfurther analysis. For other embodiments, however, output signals from asub-array (i.e., only a portion) of the elements of the two dimensionaldetector are recorded or transmitted to a processor for furtheranalysis. In this way, it is possible to select a subset of thetwo-dimensional detector for use in detecting or sensing acharacteristic of a particle. In a specific embodiment, only a portionof the output signals of the sub-array are utilized in determining acharacteristic of a particle. Such a region of interest is useful, forexample, for producing better size resolution of detected particlesand/or preventing growth of the sample volume undergoing detection.

For example, the entire two-dimensional detector may image the entireflow cell of a particle detection system. A specific sub-array maycorrespond to output signals of an imaged region of a flow cell, forexample the region of the flow cell illuminated by a beam ofelectromagnetic radiation. As another example, a sub-array maycorrespond to output signals of an imaged region of a flow cellilluminated by a beam of electromagnetic radiation but excluding thewalls of the flow cell. A region of interest, for example, may compriseoutput signals corresponding to the imaged region of a flow cellilluminated by the center of the beam of electromagnetic radiationand/or where the intensity of the beam of electromagnetic radiation issubstantially uniform.

STATEMENTS REGARDING INCORPORATION BY REFERENCE AND VARIATIONS

All references throughout this application, for example patent documentsincluding issued or granted patents or equivalents; patent applicationpublications; and non-patent literature documents or other sourcematerial; are hereby incorporated by reference herein in theirentireties, as though individually incorporated by reference, to theextent each reference is at least partially not inconsistent with thedisclosure in this application (for example, a reference that ispartially inconsistent is incorporated by reference except for thepartially inconsistent portion of the reference). U.S. ProvisionalApplications 61/005,336, 60/992,192 and 61/107,397 filed on Dec. 4,2007, Dec. 4, 2007 and Oct. 22, 2008, respectively, are hereinincorporated by reference in their entireties. U.S. NonprovisionalApplication entitled “Two-Dimensional Optical Imaging Methods andSystems for Particle Detection” by inventors Mitchell, Sandberg, Sehler,Williamson and Rice and having attorney docket number 171-07 and filedon Dec. 2, 2008 is herein incorporated by reference in its entirety.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. References cited herein are incorporated byreference herein in their entirety to indicate the state of the art, insome cases as of their filing date, and it is intended that thisinformation can be employed herein, if needed, to exclude (for example,to disclaim) specific embodiments that are in the prior art. Forexample, when a compound is claimed, it should be understood thatcompounds known in the prior art, including certain compounds disclosedin the references disclosed herein (particularly in referenced patentdocuments), are not intended to be included in the claim.

When a group of substituents is disclosed herein, it is understood thatall individual members of those groups and all subgroups, including anyisomers and enantiomers of the group members, and classes of compoundsthat can be formed using the substituents are disclosed separately. Whena compound is claimed, it should be understood that compounds known inthe art including the compounds disclosed in the references disclosedherein are not intended to be included. When a Markush group or othergrouping is used herein, all individual members of the group and allcombinations and subcombinations possible of the group are intended tobe individually included in the disclosure.

Every formulation or combination of components described or exemplifiedcan be used to practice the invention, unless otherwise stated. Specificnames of compounds are intended to be exemplary, as it is known that oneof ordinary skill in the art can name the same compounds differently.When a compound is described herein such that a particular isomer orenantiomer of the compound is not specified, for example, in a formulaor in a chemical name, that description is intended to include eachisomers and enantiomer of the compound described individual or in anycombination. One of ordinary skill in the art will appreciate thatmethods, device elements, starting materials, and synthetic methodsother than those specifically exemplified can be employed in thepractice of the invention without resort to undue experimentation. Allart-known functional equivalents, of any such methods, device elements,starting materials, and synthetic methods are intended to be included inthis invention. Whenever a range is given in the specification, forexample, a temperature range, a time range, or a composition range, allintermediate ranges and subranges, as well as all individual valuesincluded in the ranges given are intended to be included in thedisclosure.

As used herein, “comprising” is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps. As usedherein, “consisting of” excludes any element, step, or ingredient notspecified in the claim element. As used herein, “consisting essentiallyof” does not exclude materials or steps that do not materially affectthe basic and novel characteristics of the claim. Any recitation hereinof the term “comprising”, particularly in a description of components ofa composition or in a description of elements of a device, is understoodto encompass those compositions and methods consisting essentially ofand consisting of the recited components or elements. The inventionillustratively described herein suitably may be practiced in the absenceof any element or elements, limitation or limitations which is notspecifically disclosed herein.

The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention in the useof such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments and optional features, modification and variation of theconcepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

1-38. (canceled)
 39. A particle detection system comprising: a flow cell for containing a fluid flowing through said flow cell in a flow direction; a source for generating a beam of electromagnetic radiation having a cross sectional profile having a major axis and a minor axis, said source positioned to direct said beam through said flow cell, wherein an angle between said major axis and said flow direction is non-orthogonal, wherein particles contained within said fluid interact with said beam, thereby generating scattered or emitted electromagnetic radiation; a system of optics for collecting and directing said scattered or emitted electromagnetic radiation onto a two-dimensional detector, wherein said system of optics has an optical axis positioned non-orthogonal to said major axis; and said two-dimensional detector positioned in optical communication with said flow cell for receiving at least a portion of said scattered or emitted electromagnetic radiation, wherein said two-dimensional detector is positioned non-orthogonal to said optical axis of said system of optics.
 40. The particle detection system of claim 39, wherein said two-dimensional detector comprises an array of detector elements positioned such that a plurality of said detector elements receives said scattered or emitted electromagnetic radiation.
 41. The particle detection system of claim 39, wherein said angle is selected from the range of 5° to 85°.
 42. The particle detection system of claim 39 wherein said cross sectional profile has a shape that is elliptical or rectangular.
 43. The particle detection system of claim 39, wherein said cross sectional profile has a width along said minor axis selected from between 5 μm and 100 μm.
 44. The particle detection system of claim 39, wherein said cross sectional profile has a width along said major axis selected from between 50 μm and 1200 μm.
 45. The particle detection system of claim 39, wherein said cross sectional profile has a width along said major axis extending to or beyond edges of said flow cell.
 46. The particle detection system of claim 39, wherein said flow cell has a cross sectional profile having a first longer side parallel to a propagation axis of said beam and a second shorter side perpendicular to said propagation axis of said beam.
 47. The particle detection system of claim 46, wherein said first longer side has a width selected from 0.25 mm to 10 mm.
 48. The particle detection system of claim 46, wherein said second shorter side has a width selected from 80 μm to 500 μm.
 49. The particle detection system of claim 46, wherein an aspect ratio of said flow cell is greater than or equal to
 20. 50. The particle detection system of claim 39, wherein a propagation axis of said beam is orthogonal to said flow direction.
 51. The particle detection system of claim 39, wherein a propagation axis of said beam is non-orthogonal to said flow direction.
 52. The particle detection system of claim 39, wherein said system of optics images said scattered or emitted radiation onto said two-dimensional detector.
 53. The particle detection system of claim 39, wherein said scattered or emitted electromagnetic radiation is focused by said system of optics to a spot on said two-dimensional detector having a size selected from between 5 μm to 80 μm.
 54. The particle detection system of claim 39, wherein said two-dimensional detector has an orientation positioned to allow for a sharply focused image of said scattered or emitted electromagnetic radiation across an active area of said two-dimensional detector.
 55. The particle detection system of claim 39, wherein said two-dimensional detector has an orientation positioned for providing a spatially resolved image of said scattered or emitted electromagnetic radiation, wherein said scattered or emitted electromagnetic radiation is spatially resolved along a first axis parallel to a propagation axis of said beam and a second axis parallel to said major axis of said cross sectional profile of said beam.
 56. The particle detection system of claim 39, wherein said two-dimensional detector performs time delay integration.
 57. A method of detecting particles, said method comprising the steps of: providing particles in a fluid having a flow direction; passing a beam of electromagnetic radiation having a cross sectional profile having a major axis and a minor axis through said fluid, wherein an angle between said major axis and said flow direction is non-orthogonal, and wherein said particles interact with said beam thereby generating scattered or emitted electromagnetic radiation; collecting and directing said scattered or emitted electromagnetic radiation onto a two-dimensional detector using system of optics wherein said system of optics has an optical axis positioned non-orthogonal to said major axis; and detecting at least a portion of said scattered or emitted electromagnetic radiation using said two-dimensional detector, wherein said two-dimensional detector is positioned non-orthogonal to said optical axis of said system of optics, thereby detecting said particles.
 58. A method of spatially resolving an interaction of particles with a beam of electromagnetic radiation, said method comprising the steps of: providing particles suspended within a fluid flowing in a flow direction; passing a beam of electromagnetic radiation through said fluid, wherein said beam has a cross sectional profile having a major axis and a minor axis and wherein an angle between said major axis and said flow direction is non-orthogonal, and wherein said particles interact with said beam thereby generating scattered or emitted electromagnetic radiation; collecting and directing said scattered or emitted electromagnetic radiation onto a two-dimensional detector using system of optics, wherein said system of optics has an optical axis positioned non-orthogonal to said major axis, wherein said two-dimensional detector is positioned non-orthogonal to said optical axis of said system of optics, detecting at least a portion of said scattered or emitted electromagnetic radiation using said two-dimensional detector, thereby spatially resolving said scattered or emitted electromagnetic radiation in a first direction parallel to a propagation axis of said beam and in a second direction parallel to said major axis of said cross sectional profile of said beam.
 59. A method of sizing a particle, the method comprising the steps of: providing a particle suspended within a fluid flowing in a flow direction through a flow cell; passing a beam of electromagnetic radiation through said fluid, wherein said beam has a cross sectional profile having a major axis and a minor axis and wherein an angle between said major axis and said flow direction is non-orthogonal, and wherein said particle interacts with said beam thereby generating scattered or emitted electromagnetic radiation; collecting and directing said scattered or emitted electromagnetic radiation onto a two-dimensional detector using a system of optics, wherein said system of optics has an optical axis positioned non-orthogonal to said major axis, wherein said two-dimensional detector is positioned non-orthogonal to said optical axis of said system of optics, imaging at least a portion of said scattered or emitted electromagnetic radiation onto the two-dimensional detector; determining an intensity of said scattered or emitted electromagnetic radiation imaged onto said two-dimensional detector; and comparing said intensity of said scattered or emitted electromagnetic radiation imaged onto said two-dimensional detector with one or more threshold reference values, thereby determining a size of said particle. 